An Inhaled Microbiome-Targeted Biotherapeutic for Treatment of COPD

一种吸入性微生物组靶向生物治疗药物，用于治疗慢性阻塞性肺病

基本信息

批准号：
10600887
负责人：
Teodora NICOLA
金额：
$ 29.53万
依托单位：
RESBIOTIC, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10600887
关键词：
Acetylation Acute Address Adrenal Cortex Hormones Affect American Animals Anti-Inflammatory Agents Bacteria Biological Response Modifier Therapy Biology Bronchodilator Agents Cause of Death Cell Culture Techniques Cell model Cells Cessation of life Chemicals Chronic Chronic Obstructive Pulmonary Disease Chronic lung disease Collaborations Combined Modality Therapy Complementary therapies Data Degenerative Disorder Development Disease Disease Progression Disease model Dose Drug Formulations Dryness Epithelial Cells Extracellular Matrix Extracellular Matrix Degradation Formulation Frequencies Future Gelatinase B Generations Glycine Goals Health Status Human In Vitro Inflammation Inflammatory Inhalation Inhalation Device Interleukin-1 beta Interleukin-8 Lactic acid Lactobacillus Lactobacillus acidophilus Lactobacillus casei rhamnosus Lactobacillus plantarum Lead Legal patent Leukocyte Elastase Licensing Lipopolysaccharides Lung Lung diseases Mammals Modality Modeling Monitor Mus Particle Size Patients Peptide Hydrolases Peptides Peptidoglycan Persons Pharmaceutical Preparations Phase Phosphodiesterase Inhibitors Pneumonia Powder dose form Probiotics Process Production Proline Property Proteobacteria Pulmonary Inflammation Quality of life Research Respiratory Disease Respiratory Stimulants Safety Smoking Symptoms TNF gene Teichoic Acids Testing Therapeutic Toxicology Woman airway remodeling alternative treatment bronchial epithelium chemical stability chemokine chronic inflammatory lung disease clinical efficacy commercialization comparison control cytokine density dosage drug development drug inhalation dysbiosis efficacy evaluation efficacy study efficacy testing exosome experience exposed human population first-in-human improved in vivo lead candidate lung microbiome men microbial microbiome microbiome alteration microbiome research mortality risk mouse model neutrophil pharmacokinetics and pharmacodynamics pre-clinical preclinical study pulmonary function recruit safety assessment safety testing screening side effect standard of care therapeutic candidate tobacco smoke exposure treatment response

项目摘要

PROJECT SUMMARY - ResBiotic Inc. is developing its lead drug product, RB1000, a spray-dried powder com- prised of an inhaled biotherapeutic API for treatment of neutrophilic inflammation and disease progression in COPD patients. COPD is a chronic degenerative disease that is the fourth leading cause of death in the U.S., where it predominantly results from tobacco smoke exposure. Acute exacerbations are a sudden worsening of symptoms that can occur frequently, ≥ 2 per year in severe cases, and can result in reduced lung function, reduced health status, and increased risk for mortality. Treatment approaches including short- and long-acting bronchodilators, corticosteroids, phosphodiesterase inhibitors, cytokine blockers, and respiratory stimulants have been used but with limited clinical efficacy. Inhaled corticosteroids are used specifically to treat inflamma- tion but have potential for serious side effects, e.g., severe pneumonia and death. Combination therapies have demonstrated modest reductions in exacerbation frequency, but there is still significant room for improvement, as these therapeutics do not halt disease progression and often can have serious side effects. Recent research has demonstrated a strong association between neutrophilic inflammation that results from dysbiosis, i.e., an altered microbiome, of the lung in COPD. ResBiotic has demonstrated that heightened levels of proteobacteria can increase expression of matrix metalloproteinase 9 (MMP-9) and neutrophil elastase (NE), which are associ- ated with neutrophilic inflammation and can cause extracellular matrix degradation and airway remodeling. Res- Biotic has demonstrated in vitro and in vivo that anti-inflammatory Lactobacillus strains can reduce inflammation resulting from dysbiosis, including the expression of MMP-9 and NE, which may enable highly effective biother- apeutic drugs for COPD. Commercialization of a Lactobacillus-based biotherapeutic drug would provide an al- ternative anti-inflammatory approach with a different mechanism of action than currently available therapeutics. The goal of this proposal will be to develop a biotherapeutic drug that includes non-living components of a Lac- tobacillus bacterial extract that are responsible for the therapeutic response. Phase I will include screening dif- ferent cellular components at various dosages to identify several candidates that reduce MMP-9 expression in primary human bronchial epithelial cells taken from COPD patients. Phase II will include the development of a dry powder formulation of optimal candidates and safety and efficacy testing in preclinical mouse models of COPD. The deliverable for Phase II will be a lead candidate that has demonstrated efficacy in reduction of neutrophilic inflammation and improvements in lung function that is ready to advance to IND-enabling large mammal studies. Successful commercialization of the inhaled drug product RB1000 is expected to provide an alternative or complementary treatment modality to the standard of care to address neutrophilic inflammation resulting from dysbiosis in COPD, which is expected to reduce COPD exacerbations, potentially reduce disease progression, and improve patient quality of life.

Project摘要-Resbiotic Inc.正在开发其铅药物RB1000，这是一种喷雾干燥的粉末调查被遗传的生物治疗API珍贵，用于治疗中性粒细胞炎症和疾病进展 COPD患者。 COPD是一种慢性退化性疾病，是美国第四大死亡原因，它主要是由烟草烟雾暴露引起的。急性加重是突然的必需品可能经常出现的症状，每年≥2例，在严重的情况下，可能导致肺功能降低，降低了健康状况，并增加了死亡率的风险。治疗方法包括短效和长效支气管扩张剂，皮质类固醇，磷酸二酯酶抑制剂，细胞因子阻滞剂和呼吸刺激剂已使用但临床效率有限。吸入的皮质类固醇专门用于治疗炎症但具有严重副作用的潜力，例如严重的肺炎和死亡。组合疗法具有在加剧频率中显示出适度的减少，但仍有很大的改进空间由于这些治疗学不会停止疾病的进展，并且经常会产生严重的副作用。最近的研究已经证明了嗜中性炎性炎症之间的密切相关，这是由营养不良引起的，即 COPD中肺的微生物组改变。 Rebiotic已证明蛋白杆菌水平升高可以增加基质金属蛋白酶9（MMP-9）和中性粒细胞弹性酶（NE）的表达，它们是缔合的患有嗜中性炎症的炎症，可能导致细胞外基质降解和气道重塑。 res- 生物在体外和体内证明了抗炎乳杆菌菌株可以减轻炎症由营养不良引起的，包括MMP-9和NE的表达，这可能使高效的Biother- COPD的猿类药物。基于乳杆菌的生物治疗药物的商业化将提供与当前可用的治疗相比，具有不同作用机理的三元性抗炎方法。该提案的目的是开发一种生物治疗药物，其中包括lac的非生存成分造成治疗反应的烟菌提取物。第一阶段将包括筛选在各种剂量下的细胞成分，以识别几种降低MMP-9表达的候选者原发性人支气管上皮细胞从COPD患者中取。第二阶段将包括开发在临床前小鼠模型中，最佳候选者的干粉公式以及安全性和有效测试 COPD。第二阶段的交付将是一名主要候选人，在降低中性粒细胞炎症和肺功能的改善，准备向大型发展哺乳动物研究。预计继承药物RB1000的成功商业化将提供护理标准的替代或完整的治疗方式，以解决中性粒细胞炎症 COPD中的营养不良导致，预计会减少COPD加剧，可能会减少疾病进展并提高患者生活质量。